Regulation of glutamate receptors by calcium-dependent protein kinases

神经电路及其动态变化控制行为。神经回路是 由数十亿个神经元组成，这些神经元在突触上通过 突触传递，神经递质被释放并与其结合 各自的受体。突触传递可以被神经元持久地改变 在称为突触可塑性的过程中的活动，作用于动态地调节动物 行为。相反，突触可塑性的失调会导致多种 精神和认知障碍，包括自闭症、精神分裂症、精神发育迟滞、 还有毒瘾。因此，适当的突触可塑性对人类健康至关重要。其中 各种类型突触的可塑性，NMDAR(NMDAR)长期依赖 增强效应(LTP)已被广泛研究。在这种形式的LTP中，NMDAR激活 通过激活CaMKII增加突触AMPA受体(AMPAR)的活性 将AMPAR从预备池驱动到突触。虽然有100多个分子 都与LTP有关，但直接的细胞机制仍不清楚。最近， 我们确定TARP-8是LTP的关键底物。在这个提案中，我们的目标是 揭示突触可塑性过程中AMPAR增强的基本机制。 该提案的成功完成将为以下方面提供基本的机械性见解 LTP及其在控制动物行为中的作用。认为突触可塑性是一种 调节动态脑功能的通用模型，阐明其分子机制 对突触可塑性的控制将使我们能够识别可能的分子 减轻精神和认知障碍的药物靶标。此外， 识别直接控制突触可塑性的关键分子是首要任务 神经生物学目标。

Neural circuits and their dynamic alteration control behavior. Neural circuits are composed of billions of neurons that communicate at synapses via the process of synaptic transmission, whereby neurotransmitters are released and bind to their respective receptors. Synaptic transmission can be persistently modified by neuronal activity in a process termed synaptic plasticity, acting to dynamically modulate animal behavior. Conversely, dysregulation of synaptic plasticity contributes to various psychiatric and cognitive disorders including autism, schizophrenia, mental retardation, and addiction. Therefore, proper synaptic plasticity is crucial for human health. Among various types of synaptic plasticity, NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) has been extensively studied. In this form of LTP, NMDAR activation increases synaptic AMPA receptor (AMPAR) activity through activation of CaMKII that drives AMPARs from a reserve pool to synapses. Though more than 100 molecules have been implicated in LTP, the direct cellular machinery remains unclear. Recently, we identified TARP-8 as a critical CaMKII substrate for LTP. In this propsal, we aim to reveal the fundamental mechanisms of AMPAR potentiation during synaptic plasticity. Successful completion of this proposal will provide fundamental mechanistic insights into LTP and its roles in controlling animal behavior. Considering synaptic plasticity as a general model to mediate dynamic brain function, elucidating the molecular mechanisms underlying the control of synaptic plasticity will enable us to identify putative molecular targets for drugs to alleviate psychiatric and cognitive disorders. Moreover, the identification of the critical molecules that control synaptic plasticity directly is a chief neurobiological goal.